Researchers 'a step closer' to universal flu vaccine

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Behind the Headlines

Tuesday August 25 2015

Could a one-size jab fit all?

"Universal flu vaccine comes closer, scientists say," BBC News reports after two independent teams of researchers each found ways to target multiple strains of the influenza virus – but, as yet, the research has only involved animals.

Because there are many different strains of flu and they constantly change, people need to be vaccinated with a different flu vaccine every flu season. Scientists would like to be able to develop a universal flu vaccine that would be active against all strains of the virus.

The studies developed two different vaccines. Both vaccines were able to protect mice against what would usually be a lethal dose of flu, and one vaccine reduced fever symptoms in monkeys. Both vaccines were based on the principle of attacking specific sites on the virus that are less likely to mutate as new strains come along.

This analysis focuses on the second study, which advanced as far as testing on monkeys, as these results are more likely to apply to humans.

We can't yet be certain that the vaccines will be effective or safe until they are tested on humans, and more animal and lab research will be needed before this can be started.

However, it seems likely that this avenue of research could eventually lead to better flu vaccines at some point in the future. Until then, one simple way to reduce your chances of getting flu is to regularly wash your hands.

Where did the story come from?

One of the studies was carried out by researchers from the Crucell Vaccine Institute at the Janssen Center of Excellence for Immunoprophylaxis in the Netherlands and other research centres in the US.

Some parts of the study were supported by the US Department of Energy, National Institutes of Health and National Institute of General Medical Sciences. Various companies provided supplies or input into early designs.

The authors noted that Crucell Holland B.V., a Janssen company, has pending patent applications in this area of research.

The second study was carried out by researchers from the National Institutes of Health in the US, BIOQUAL Inc, and Osaka University in Japan. A patent application has been filed as a result of the study. It was published in the peer-reviewed journal Nature Medicine.

In general, UK news sources have covered the story well, pointing out that the research was in animals and that human vaccines based on this research may still take years to develop.

What kind of research was this?

This laboratory and animal research aimed to develop a universal flu vaccine. There are many different flu strains and the flu virus is constantly changing.

This has meant that people need to be vaccinated with a different flu vaccine every flu season, which is targeted at the strain or strains expected to be circulating at that time. Scientists would like to be able to develop a universal flu vaccine that would be active against all – or at least most – strains.

This animal research is an essential first step towards developing human vaccines, identifying whether the vaccines look safe and effective enough to go on to human trials. These animal studies usually start in smaller animals such as mice, and if they are successful go on to be tested in primates, whose biology is more similar to humans'.

What did the research involve?

The flu virus is shaped like a ball, with many "spikes" sticking out of its surface made of a chemical called haemagglutinin. The "stem" part of this spike does not change as much as its tip or other parts of the virus, so both of these studies aimed to develop a vaccine that targeted the stem.

Broadly neutralising antibodies have been discovered in humans, and are active against many flu viruses. Most of them bind to the haemagglutinin stem.

The researchers therefore wanted to create a vaccine that would mimic a section of this stem to stimulate the immune system to produce these types of antibodies. This would prepare the immune system to deal with different types of flu virus in the future.

The first study developed various candidate molecules based on different parts of the haemagglutinin stem using a form of haemagglutinin called HA1. Researchers tested whether the molecules showed similar structures to the corresponding part of the stem in an intact virus, and whether they could bind to antibodies against the stem.

Based on this, they picked the best candidate molecules for testing as vaccines on animals. First, the researchers vaccinated mice, then injected them with what would usually be a lethal dose of flu virus, to see whether they died. In these experiments, they used various different strains of flu to see how well the vaccine protected against them.

The researchers then tested the best-performing vaccine in crab-eating macaques – a type of monkey found in southeast Asia. They injected six monkeys with three doses of the vaccine, and then injected them with a non-lethal dose of flu virus.

They also injected the flu virus into 12 control monkeys. Half of the control monkeys received a human flu vaccine, while the other half received dummy inactive injections. The researchers looked at how ill-vaccinated and unvaccinated monkeys became.

The people assessing the mice and monkeys were not blinded as to which vaccine the animals received – ideally, they would have been blinded to ensure their views could not influence the results.

The researchers also looked at whether the antibodies the vaccinated mice and monkeys were producing bound to a wide range of different flu virus strains in the lab. The antibodies need to be able to bind to the virus strains to have an effect in fighting them.

In the second study, researchers carried out similar experiments to develop and select a candidate molecule based on the H1 haemagglutinin stem region to use as a vaccine. This vaccine, called H1-SS-np, utilised this molecule to bind to tiny particles of a chemical called ferritin (nanoparticles). The researchers then tested it in mice and ferrets.

What were the basic results?

The first study found good candidate molecules produced high levels of an immune response when injected into mice, which is needed if a vaccine is going to work. Some of the vaccines gave better protection against a potentially lethal dose of flu than others.

One molecule, called mini-HA #4900, prevented 90% of the vaccinated mice from dying after one injection, and after two injections all vaccinated mice survived without losing weight or showing flu symptoms. It showed this protection against an H1N1 flu virus, which is a different H1 strain from the one used to develop the molecule, as well as an H5N1 strain, which has a different type of haemagglutinin.

The researchers went on to test mini-HA #4900 in monkeys. The vaccine again produced high levels of immune response. The antibodies produced could bind to a wide range of different flu virus strains in the lab, including H1 strains and H5N1, as well as some – but not all – group 2 flu viruses. Group 2 viruses have a different haemagglutinin structure from group 1 viruses such as H1N1 and H5N1.

Monkeys vaccinated with mini-HA #4900 had less fever in the first three to eight days after exposure to the flu virus than those vaccinated with either the dummy or human flu vaccines. One of the monkeys in the mini-HA #4900 group was excluded from the analysis because data collection failed.

The second study also identified a candidate vaccine that could produce antibodies in mice and ferrets, which reacted against a variety of flu strains. The vaccine could fully protect mice against a lethal dose of H5N1 flu, and partially protected the ferrets.

How did the researchers interpret the results?

The researchers in the first study concluded that, "These results provide proof of concept for design of [haemagglutinin] stem mimics that elicit [broadly neutralising antibodies] against influenza A group 1 viruses."

Conclusion

These studies have developed two different flu vaccines that could potentially offer broader protection against a variety of flu strains than current vaccines.

As yet, this research has only been conducted in animals, with one study showing an effect against different flu strains in mice and monkeys, and the other showing an effect in mice and ferrets.

As monkeys are more similar to humans than mice or ferrets, the results from these experiments are likely to be the most representative of what would happen in humans.

While the results are encouraging, it is likely that additional lab and animal research on both vaccines will be undertaken to ensure the vaccine's safety and effectiveness before they reach testing on humans. The results suggest that while the vaccines may provide broad protection, they still may not be able to protect against all flu viruses.

As there are many different flu strains and the flu virus is constantly changing, different flu vaccines are needed every flu season. Research like this aims to get us close to a universal flu vaccine that would be active against all – or at least most – strains.

While the vaccines tested in these studies have not yet proven to be effective in humans, it seems likely that this type of research could eventually lead to better flu vaccines.

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